Corticostriatal BDNF signaling in alcohol seeking and preference switching

项目总结 大多数美国成年人至少饮酒一次。然而，在这一人群中， 只有10%-15%的人患上酒精使用障碍(AUD)，这表明大多数人可能天生就不会 酗酒。脑源性神经营养因子(BDNF)通过酪氨酸受体激酶B(TrkB)的信号传导 受体在防止酒精摄入量上升到过高水平方面起着作用。这项研究的目的是 就是建立BDNF阻止饮酒的机制和神经回路。BDNF- 表达从眶前皮质(OFC)到背侧纹状体(DS)的神经元投射 罗恩实验室以前展示过，它可以控制小鼠的酒精摄入量。OFC参与了更新 并对奖赏价值和DS进行排名，这对于习惯性或目标导向行动的发展是必要的-- 选拔策略。我最近发现，全身注射TrkB激动剂可以恢复习惯性酒精 在小鼠身上寻求更具目标导向的行为。因此，我假设BDNF信号的作用 在DS中，特别是在OFC-DS电路中，是使行为偏离习惯性饮酒 以及更多以目标为导向的酗酒和替代奖励。 使用创新的分子、药理学和行为学方法，我将测试以下目标： 目的1研究OFC中表达BDNF的神经元在促进目标导向中的作用 酗酒。我将训练表达Cre重组酶的转基因小鼠在表达BDNF的神经元中 习惯性地自行饮酒。然后，我将使用化学发生策略来特异性地激活BDNF- 在OFC内表达神经元以确定BDNF阳性的OFC神经元活性是否足以转移 小鼠从习惯性饮酒转变为目标导向的饮酒。 目标2将研究BDNF信号在习惯性饮酒的DS和OFC-DS回路中的作用 寻找。我将利用药理学工具和电路特异性基因干预来激活或抑制BDNF 在DS和OFC-DS电路中发送信号，并确定这些操作对习惯的影响 与目标导向的酒精寻求行动选择策略在小鼠中的对比。 目标3将确定在OFC-DS投射中BDNF信号在“偏好转换”中的作用 饮酒和社交之间的关系。为了验证这一假设，我将使用新的行为分析来 评估饮酒和社交寻求行为的差异，并伴随着药物和 改变内源性皮质纹状体内脑源性神经营养因子信号的电路特异性遗传操作。 如果成功，这项工作将为BDNF信号保持酒精的机制提供洞察力 适量饮酒，为AUD的未来治疗干预提供潜在靶点。

PROJECT SUMMARY Most adults in the United States have consumed alcohol at least once. Within that population, however, only 10-15% develop alcohol use disorder (AUD), indicating that majority may be intrinsically protected against alcohol addiction. Brain-derived neurotrophic factor (BDNF) signaling via the tyrosine-receptor kinase B (TrkB) receptor plays a role in preventing the escalation of alcohol intake to excessive levels. The goal of this study is to establish the mechanisms and neural circuitry by which BDNF gates alcohol drinking. BDNF- expressing neuronal projections from the orbitofrontal cortex (OFC) to the dorsal striatum (DS) have been shown previously by the Ron laboratory to gate alcohol consumption in mice. The OFC is involved in updating and ranking reward values and the DS is necessary for the development of habitual or goal-directed action- selection strategies. I recently found that that systemic administration of a TrkB agonist reverts habitual alcohol seeking toward more goal-directed behavior in mice. I therefore hypothesize that the role of BDNF signaling in the DS, and specifically in OFC-DS circuitry, is to bias behavior away from habitual alcohol seeking and toward more goal-directed alcohol seeking and alternative rewards. Using innovative molecular, pharmacologic and behavioral approaches, I will test the following aims: Aim 1 will investigate the role of BDNF-expressing neurons in the OFC in promoting goal-directed alcohol seeking. I will train transgenic mice expressing Cre-recombinase in BDNF-expressing neurons to habitually self-administer alcohol. I will then use a chemogenetic strategy to specifically activate BDNF- expressing neurons in the OFC to determine whether BDNF-positive OFC neuronal activity is sufficient to shift mice from habitual to goal-directed alcohol seeking. Aim 2 will examine the role of BDNF signaling in the DS and in the OFC-DS circuit in habitual alcohol seeking. I will utilize pharmacological tools and circuit-specific genetic interventions to activate or inhibit BDNF signaling in the DS and in OFC-DS circuits and determine the effects these manipulations have on habitual versus goal-directed alcohol seeking action-selection strategies in mice. Aim 3 will establish the effects of BDNF signaling in the OFC-DS projection on “preference-switching” between alcohol intake and social interaction. To test this hypothesis, I will use novel behavioral assays to assess differences in alcohol- and social interaction-seeking behaviors accompanied with pharmacological and circuit-specific genetic manipulations to alter endogenous corticostriatal BDNF signaling. If successful, this work will provide insight into the mechanism by which BDNF signaling keeps alcohol drinking in moderation and provide potential targets for future therapeutic interventions for AUD treatment.